The present invention relates to the general field of pharmaceutical arts. More specifically, the invention relates to pharmaceutical gel and aerosol formulations made from film-forming water-insoluble polymers.
Bioadhesive pharmaceutical formulations can be used to deliver drugs locally at the site of application or systemically through absorption from the site of application. In either type of intended delivery, one primary requirement is that an effective concentration of the particular pharmaceutical be maintained at the site of application for a sufficient period of time such that the pharmaceutical can act locally or be absorbed for systemic effects.
Given the tendency of natural bodily fluids to rapidly wash away topically applied pharmaceutical components, topical application to wet mucosal surfaces or other body tissues has been problematic. For example, in the mouth, saliva, natural replacement of the mucosal surface, and movements associated with eating, drinking, and speaking are some of the factors that have limited the effectiveness and residence time of pharmaceutical carriers.
Bioadhesive formulations are known in the art and include gels, pastes, tablets, and films. For example, U.S. Pat. Nos. 5,192,802, 5,314,915, 5,298,258, and 5,642,749 describe bioadhesive gels. Denture adhesive pastes are described in, for example, U.S. Pat. Nos. 4,894,232 and 4,518,721. A commercial product under the name Orabase(copyright)-B, which is a thick gel or paste for the relief of mouth sores, is another example of an adhesive paste. Bioadhesive tablets are described in U.S. Pat. Nos. 4,915,948, 4,226,848, 4,292,299, and 4,250,163, as having single layer or bilayers. U.S. Pat. Nos. 3,996,934 and 4,286,592 describe the use of bandages or bioadhesive laminated films.
U.S. Pat. Nos. 4,517,173, 4,572,832, 4,713,243, 4,900,554, and 5,137,729 describe delivery systems for use on mucosal surfaces. U.S. Pat. No. 4,381,296 describes a suspension of tannic acid, salicylic acid, and boric acid in ethanol wherein no gelling agent was used.
U.S. Pat. Nos. 5,081,157 and 5,081,158 describe compositions made of hydroxypropyl cellulose, a non-toxic volatile solvent, an esterification agent, and a medicinal component. A crosslinking agent may also be used. The ""158 Patent teaches that alkyl or hydroxyalkyl substituted cellulose are not suitable substitutes for hydroxypropyl cellulose (column 2, lines 28-31) for forming films on body tissues.
Japanese Patent publication JP 56-100714 describes a preparation which comprises an uneven distribution of a medicinal layer in a coating layer by creating a tablet for mucosal adhesion. This preparation includes surfactants.
The above-described formulations appear to lack one or more preferred characteristics for an efficient and commercially acceptable bioadhesive pharmaceutical delivery device, namely, residence time at the site of application for a desired length; water-erodability; instantaneous adhesion upon application to the affected site such as mucosal surface; ease of handling and application to the affected site; ease of removal of the delivery device from the affected tissue or in a natural dissolution of the delivery device at the delivery site; and ease of comfort, with minimal foreign body sensation. Further, in all these cases, the ingredients comprising the formulation must be pharmaceutically acceptable.
More recently, pharmaceutical preparations made from film-forming water-insoluble polymers solubilized in pharmaceutically acceptable solvents, bioadhesive polymers, and at least one active pharmaceutical, and methods for their use have been described. See for example, PCT publication WO 9817252, published Apr. 30, 1998.
The above-described references, however, have not effectively addressed the issue of drug solubility in the formulation. Solubility influences a drug""s dissolution, release kinetics, and ultimately its bioavailability and thus plays a major role in the preformulation stage of many pharmaceuticals. See generally, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, CHAPTER 83, MACK PUBL. CO., EASTON (19 TH EDITION, 1995) (hereinafter, REMINGTON). Since many pharmaceuticals are not very soluble in the formulation, the number of available dosage forms is limited for such pharmaceuticals. The present invention addresses this problem and provides pharmaceutical gels and aerosol formulations that are capable of delivering drugs of varying solubility characteristics.
The present invention provides non-water soluble, film-forming bioadhesive pharmaceutical formulations comprising:
a water-insoluble alkyl cellulose from about 0.1% to about 20% by weight of the formulation;
a solvent system comprising a mixture of from about 30% to about 90% by weight of at least one volatile solvent and up to about 25% by weight of water;
a solubilization agent or a dispersing agent or a mixture thereof, and
a pharmaceutical.
The alkyl cellulose may be methyl cellulose, ethyl cellulose, propyl cellulose, or butyl cellulose, or a mixture thereof and the volatile solvent may be a lower alkyl alcohol, 1-methyl-2-pyrrolidone, a volatile silicone, a propellant, or a mixture thereof. In some aspects, the pharmaceutical is not very soluble in the formulation in the absence of a solubilization agent. The solubilization agent may be imidazole.
The formulations may further comprise a liquified gas propellant or a compressed gas propellant or a mixture thereof. In some aspects, the propellant is 1,1-difluoroethane.
Additionally, non-water soluble, film-forming bioadhesive pharmaceutical formulations are provided comprising:
ethylcellulose which constitutes from about 0.1% to about 20% by weight of the formulation;
a solvent system comprising a mixture of at least one volatile solvent and up to about 25% by weight of water; and
a pharmaceutical.
The volatile solvent may be a lower alkyl alcohol, 1-methyl-2-pyrrolidone, a volatile silicone, or a mixture thereof. In one aspect, the volatile solvent comprises ethanol.
Further, the formulations may comprise from about 1% to about 10% by weight of a polymer having bioadhesive properties, wherein said bioadhesive polymer is polycarbophil, polyacrylic acid, polyvinylpyrrolidone, sodium carboxymethyl cellulose, or a mixture thereof. In some aspects, the above formulations may further comprise an adjuvant.
The formulations may also comprise a bioerodable polymer, wherein the bioerodable polymer is hydroxypropyl cellulose or a copolymer of lactic and glycolic acids, polycaprolactone, a polyorthoester, polyphosphazene or a mixture thereof.
The formulations can be prepared such that the pharmaceutical is released in a controlled manner. In some aspects, the pH of the formulation is from about 4.0 to about 7.0.
The above formulations can be prepared in an aerosol form. In such cases, a liquified gas propellant or a compressed gas propellant or a mixture thereof can be used to deliver the formulation. In some aspects, the propellant is 1,1-difluoroethane. Alternatively, mechanical means (i.e., without a propellant) can also be used to deliver the formulation. In some aspects, water constitutes greater than about 5% by weight of the above formulations.
A broad category of drugs can be delivered using the formulations of the present invention. One specific but nonlimiting example is Amlexanox, 2-amino-7-(1-methylethyl)-5-oxo-5H-[1]benzopyrano-[2,3-b]-pyridine-3-carboxylic acid, which constitutes from about 0.5% to about 5% by weight of the formulation.
In one aspect, a non-water soluble, film-forming bioadhesive pharmaceutical formulation is provided comprising:
ethylcellulose which constitutes from about 0.1% to about 20% by weight of the formulation;
ethanol which constitutes from about 60% to about 90% by weight of the formulation;
water up to about 25% by weight of the formulation;
hydroxypropylcellulose as a bioerodable polymer constituting up to about 2% by weight of the formulation;
polyvinylpyrrolidone, polycarbophil or a mixture thereof as a bioadhesive polymer constituting from about 1% to about 10% by weight of the formulation; imidazole constituting from about 0.01% to about 5% by weight of the formulation; and
2-amino-7-(1-methylethyl)-5-oxo-5H-[1]benzopyrano-[2,3-b]-pyridine-3-carboxylic acid, which constitutes from about 0.5% to about 5% by weight of the formulation.
Methods for delivery of an effective amount of one or more pharmaceuticals to a skin surface or a mucosal surface are also provided. Such methods comprise administering one or more of the above-described formulations to the skin surface or to the mucosal surface.